Following traumatic brain injury (TBI), as well as other types of brain injury, many patients experience a state of coma in which they are unawake and unaware. Coma very rarely lasts more than two weeks, at which point patients either regain consciousness or emerge into a state of wakefulness (sleep/wake cycles, eye opening, basic reflexes) without regaining awareness of themselves or their environment. These patients suffer from Disorders of Consciousness (DoC), and their level of awareness is assessed for diagnosis into the vegetative (no awareness) or minimally conscious state (periodic increases in awareness). These diagnoses are notoriously inaccurate, offering little predictive value in prognoses. Awareness can return within weeks, years, or never. Patients? families are therefore left with unimaginably difficult decisions and little information on which to base them. Our understanding of the neural correlates and outcomes of DoC is severely lacking, due to the fact that minimal basic science investigation has been pursued. To date DoC have only been examined in clinical studies, which are often encumbered by high variability, low sample sizes, limited data output, and lack of necessary controls. To address these challenges, the proposed project will establish the first preclinical model for studying DoC to provide more accurate diagnoses and prognoses, improved inclusion criteria for clinical trials, and a platform for developing new therapeutics. Coma results from white matter damage due to rotational acceleration of the head during TBI, not from forces associated with impact or linear acceleration. Currently, the only system in the world that accurately models rotational acceleration-induced TBI is the swine injury model utilized by the Center for Brain Injury & Repair at the University of Pennsylvania. This project will apply the rotational TBI model to induce coma, and subjects will then be cared for in a swine intensive care unit and monitored for emergence into wakefulness without awareness utilizing a battery of electroencephalographic, behavioral, and other analyses. It has been hypothesized that while brainstem injury is necessary to produce coma, recovery from DoC and efficacy of treatments may be dependent upon the extent of diffuse axonal injury throughout the forebrain. Therefore, a pharmacological pontine lesion shown to produce coma in rats will be applied in swine to test whether precise white matter injury in pons is sufficient to lead to DoC. Subjects from each injury group that exhibit DoC lasting one month will be used to evaluate existing treatments for improving awareness. Specifically, deep brain stimulation will be tested in thalamus and basal forebrain, and we will administer the GABA agonist zolpidem while measuring changes in awareness. Additional data will be collected postmortem, including diffusion tensor imaging to map intact white matter tracts, and various pathological and immunochemical staining. This study will open the field of DoC to basic science for the first time, providing clinicians and families desperately needed clarity and establishing a platform for developing future therapeutics.